Rabbits and rats with HE due to FHF exhibit increased resistance to the convulsive effects of bicuculline (a GABA receptor antagonist) and 3-mercaptopropionic acid (an inhibitor of GABA synthesis), respectively. Both clinical and electrophysiologic (VER waveform) ameliorations of HE, have been induced in animals with FHF by benzodiazepine (BZ) receptor antagonists. Furthermore, spontaneous in vitro activity of Purkinje neurons from rabbits in HE due to FHF exhibited increased sensitivity to depression by agonists of the GABA/BZ receptor complex, including a BZ, and, in contrast to control neurons, exhibited excitation when exposed to BZ receptor antagonists. In addition a BZ receptor antagonist reversed the hypersensitivity of HE rabbit neurons to depression by a GABA agonist. The functional status of the chloride ionophore of the GAB/VBZ receptor complex has been shown to be normal in a rat model of HE due to FHF. Radioligand binding to BZ receptors, determined autoradiographically, was decreased in thin unwashed sections from HE rabbit brains. Purification and characterization of HE rat brain extracts revealed the presence of reversible, competitive, heat and protease stable BZ receptor ligands with agonist properties. Two of these ligands have been chemically characterized as the 1,4 BZs diazepam and N-desmethyldiazepam. The concentrations of these compounds were 2-9 fold greater in HE rat brain than control brain. Overall, these findings suggest that in HE due to FHF: (i) There is increased GABA-ergic tone; (ii) Blockading of BZ receptors can ameliorate HE; (iii) BZ receptor antagonists may be of value in the management of HE; and (iv) Endogenous BZ receptor agonists probably contribute to HE.